Project #4: The Role of Presynaptic Plasticity in Circuit Function and Behavior Long-lasting changes in synaptic efficacy are thought to mediate many of the changes in neural circuit function and behavior that occur during development, learning, and recovery from injury. Such long-term synaptic plasticity can be accomplished through either the modification of presynaptic terminals to alter the the amount of neurotransmitter released by an action potential, or through the modification of the postsynaptic machinery to alter the amplitude of the response to a given amount of transmitter. Some synapses, such as the ones we will focus on in this project, exhibit both presynaptic and postsynaptic forms of plasticity, which suggests that these processes are not simply different means to the same end. Rather, pre- and postsynaptic plasticity mechanisms may play distinct roles in the modification of signal processing in a neural circuit. A vast majority of the work on neural plasticity has focused on postsynaptic plasticity. In this Program Project, we focus on presynaptic plasticity. Projects #1-3 will investigate the molecular, biochemical, and cellular mechanisms of presynaptic plasticity. The results from those projects will yield increasingly precise tools for manipulating presynaptic plasticity in vivo. In Project #4, we will use those tools to analyze how presynaptic plasticity functions in an intact circuit, more specifically, in the well-characterized cerebellar circuit that supports motor learning in the vestibulo-ocular reflex. In Aim #1, we will conduct a detailed behavioral analysis to determine which aspects of motor learning are impaired when presynaptic plasticity is disrupted. In Aim #2, we will record in vivo from individual neurons in the cerebellum, to assess which learning-related changes in neural signaling depend on presynaptic plasticity. In Aim #3, we will perform neural network simulations to integrate the synaptic, circuit level, and behavioral results from the Program Project into a coherent model. Our experiments will help resolve some ongoing controversies about the neural mechanisms of motor learning, and also will serve as a platform for testing more general ideas about the function of presynaptic plasticity in the nervous system. Finally, our results will generate new questions about presynaptic function that can be tested in reduced preparations by our PPG collaborators.